Nampt Potentiates Antioxidant Defense in Diabetic Cardiomyopathy.

[Figure: see text].

Prediction of Slow-Flow Phenomenon After Stent Implantation Using Near-Infrared Spectroscopy in Patients With Acute and Chronic Coronary Syndrome.

BACKGROUND: The slow-flow phenomenon is associated with worse clinical outcomes after percutaneous coronary intervention (PCI), so our goal for this study was to see how predictive how near-infrared spectroscopy (NIRS) could be.Methods and Results: We enrolled 179 lesions from 152 patients who had de novo coronary stent implantation guided by NIRS-intravascular ultrasound (IVUS) (male: 69.1%, mean age: 74.3±11.5 years, acute coronary syndrome: 65.1%, diabetes: 42.1%). NIRS automatically determined the maximum 4-mm lipid core burden index (maxLCBI4 mm) value at pre- and post-PCI procedures. The slow-flow phenomenon was defined as the deterioration of TIMI (Thrombolysis in Myocardial Infarction) flows on angiography during the PCI procedure in the absence of mechanical obstruction. The slow-flow phenomenon occurred in 13 (7.3%) lesions, and the slow-flow phenomenon group had a significantly higher maxLCBI4 mm(740±147 vs. 471±223, P<0.001). The best maxLCBI4 mmcutoff point in both acute and chronic coronary syndrome was 578 and 480, with sensitivity of 100%, for predicting the slow-flow phenomenon. In the receiver-operating characteristics analysis, the area under the curve for acute and chronic coronary syndrome was 0.849 and 0.851, respectively. CONCLUSIONS: The results of this study support the utility of NIRS-IVUS-guided PCI for the prediction of the slow-flow phenomenon.

Different effects of medications for hypertension on renal function between patients with and without diabetes mellitus undergoing percutaneous coronary intervention: a retrospective single-center cohort study.

BACKGROUND: Diabetes mellitus (DM) and hypertension are well-known atherosclerosis risk factors. Furthermore, renal dysfunction is a crucial risk factor for patients with coronary artery disease (CAD), and managing renal function in these patients is complicated because of comorbid conditions and potential side effects during treatment. Therefore, this study aimed to investigate the effect of medications for hypertension on renal function after percutaneous coronary intervention (PCI) between patients with and without DM with statins. METHODS: In 297 consecutive patients undergoing PCI for stable angina pectoris, cystatin C (CysC) was evaluated at baseline and 9 months after PCI, and the percent change in CysC (%CysC) was calculated. The association of worsening renal function (WRF: %CysC ≥ 0) and baseline characteristics, including medications, was assessed. RESULTS: Among 297 hypertensive patients with statins, 196 and 101 were with and without DM, respectively. Angiotensin-converting enzyme inhibitor (ACEI), angiotensin II receptor blocker, and ß-blocker were prescribed in 56 (29%), 82 (42%), and 91 (46%) patients in the DM group, and 20 (20%), 52 (51%), and 52 (51%) in the non-DM group, respectively. The patients with WRF after PCI were 100 (51%) and 59 (58%) in the DM and non-DM groups (p = 0.261). Additionally, the %CysC had no significant differences between groups [median: 0%, interquartile range (IQR): -7.9% to 8.5% vs. median: 1.1%, IQR: -6.6% to 9.6%, p = 0.521]. Multivariate logistic analysis for WRF using relevant factors from univariate analysis showed that only ß-blocker [odds ratio (OR): 2.76, 95% confidence interval (CI): 1.03-7.90, p = 0.048] was independently associated with WRF in the DM group whereas ACEI (OR: 0.07, 95% CI: 0.01-0.47, p = 0.012) was negatively correlated with WRF in the non-DM group. CONCLUSION: The ß-blocker was the independent risk factor for WRF in patients with DM in the late phase after PCI for stable angina pectoris, while the use of ACEI had a renoprotective effect in patients without DM.

Association of wound, ischemia, and foot infection clinical stage with frailty and malnutrition in chronic limb-threatening ischemia patients undergoing endovascular intervention.

OBJECTIVE: The Wound, Ischemia, and foot Infection (WIfI) clinical stage has been thought to have a prognostic value in Chronic limb-threatening ischemia (CLTI) patients, and frailty and nutritional status appear to represent pivotal factor affecting prognosis among CLTI patients. The purpose of this study was to examine clinical factors (including frailty and nutritional status) relevant to WIfI clinical stage. METHODS: This retrospective study investigated 200 consecutive CLTI patients. We individually assessed WIfI clinical stage, frailty according to the Clinical Frailty Scale (CFS) score, and malnutrition according to Geriatric Nutritional Risk Index (GNRI). We then compared mortality after endovascular intervention between a WIfI stage 1, 2 group and a stage 3, 4 group, and investigated associations between baseline characteristics (including CFS and GNRI) and WIfI clinical stage. RESULTS: Among 200 patients, 123 patients (62%) showed WIfI stage 1 or 2, and the remaining 77 patients (38%) had WIfI stage 3 or 4. CFS score was significantly higher in the WIfI stage 3, 4 group [median 6.0, interquartile range (IQR) 5.5-7.0] compared with the WIfI stage 1, 2 group (median 5.0, IQR 4.0-6.0, p < 0.001), and GNRI was significantly lower in the WIfI stage 3, 4 group (median 88, IQR 80-97) than in the WIfI stage 1, 2 (median 103, IQR 94-111, p < 0.001). Forty patients (20%) died after endovascular intervention. Incidences of all-cause and cardiac deaths were higher in the WIfI stage 3, 4 group than in the WIfI stage 1, 2 group (27% vs. 15%, p = 0.047 and 12% vs. 3%, p = 0.040, respectively). Kaplan-Meier analysis showed a significantly lower survival rate in the WIfI stage 3, 4 group than in the WIfI stage 1, 2 group (p = 0.002 by log-rank test). Multivariate logistic regression analysis using relevant factors from univariate analysis showed CFS score [odds ratio (OR) 2.06, 95% confidence interval (CI) 1.41-3.13, p < 0.001), diabetes mellitus (OR 3.17, 95%CI 1.17-8.61, p = 0.023) and GNRI (OR 0.93, 95%CI 0.89-0.97, p = 0.002) significantly associated with WIfI stage 3 or 4. In addition, multivariate ordinal logistic regression analysis for WIfI clinical stage showed CFS score (OR 1.43, 95%CI 1.09-1.89, p = 0.011), diabetes mellitus (OR 1.77, 95%CI 1.26-2.54, p < 0.001), and high-sensitivity C-reactive protein (OR 1.14, 95%CI 1.02-1.28, p = 0.041) were positively associated with WIfI clinical stage, and GNRI correlated negatively with WIfI clinical stage (OR 0.95, 95%CI 0.91-0.97, p < 0.001). CONCLUSIONS: These results indicate that CLTI patients with high WIfI clinical stage may be more frail and malnourished, and be associated with poor prognosis after endovascular intervention.

Risk Factors for Vulnerable Plaque Detected Using Near-Infrared Spectroscopy in Patients Receiving Statin Therapy with No History of Coronary Artery Disease.

Residual risk of atherosclerosis remains high despite the use of lipid-lowering therapy with statins. Near-infrared spectroscopy intravascular ultrasound imaging (NIRS-IVUS) can identify vulnerable plaque via the detection of lipid-rich plaque. This study aimed to reveal the clinical characteristics of patients with vulnerable plaque despite statin therapy.NIRS-IVUS was used to determine the maximum 4 mm Lipid Core Burden Index (MaxLCBI4 mm) values of 38 de novo culprit lesions from 32 patients with acute coronary syndrome (53%) (mean age: 73.1 ± 13.1 years) who underwent percutaneous coronary intervention after a minimum 6 months of statin therapy for primary prevention. A patient with vulnerable plaque was defined as an individual presenting at least 1 target lesion with a vulnerable plaque (MaxLCBI4 mm > 400). Overall, the average low-density lipoprotein cholesterol (LDL-C) level was 95.5 ± 27.2 mg/dL. Patients in the vulnerable plaque group were younger and had higher LDL-C, triglycerides, and non-high-density lipoprotein cholesterol (HDL-C) levels than those in the non-vulnerable plaque group. The MaxLCBI4 mm was positively correlated with LDL-C (P = 0.0002), triglycerides (P = 0.0003), and non-HDL-C (P = 0.0001). In multivariate analysis, all 3 treatable lipid components failed to show an independent relationship with the patients with vulnerable plaque. Using receiver-operating characteristics curve analysis, the cutoff points for LDL-C, triglycerides, and non-HDL-C were determined to be 78 mg/dL, 108 mg/dL, and 111 mg/dL, respectively, at MaxLCBI4 mm > 400. In conclusion, this study supports a more comprehensive and aggressive lipid-lowering therapy for the primary prevention of coronary artery disease.

Cardio-Ankle Vascular Index and Left Atrial Reverse Remodeling After Ablation for Atrial Fibrillation.

Arterial stiffness has been reported to cause left atrial (LA) remodeling due to increased left ventricular filling pressure, resulting in atrial fibrillation (AF). This study aimed to evaluate the association between LA reverse remodeling (LARR) after AF ablation and cardio-ankle vascular index (CAVI), an indicator of arterial stiffness.This study included 333 patients with AF (171 with paroxysmal AF and 162 with nonparoxysmal AF) and LA enlargement (LA volume index ≥ 34 mL/m2) who underwent AF ablation between December 2008 and July 2021. CAVI was evaluated preoperatively during AF (n = 155, 46.5%) or sinus rhythm (n = 178, 53.5%). Participants were divided into groups with LARR (n = 133, 39.9%) and without LARR (n = 200, 60.1%) according to whether the degree of decrease in LA volume index on transthoracic echocardiography 6 months after ablation was ≥ 15% or < 15%, respectively.Sinus rhythm was maintained in 168 (50.5%) patients within 3-6 months after the index procedure. Univariate analysis revealed that preoperative CAVI (7.80 ± 1.22 versus 8.57 ± 1.09, P < 0.001) was significantly lower, and the maintenance of sinus rhythm (61.6% versus 43.0%, P = 0.0011) was higher in the group with LARR. Multivariate logistic regression analysis revealed that preoperative CAVI was independently associated with LARR (odds ratio, 0.60, 95% confidence interval, 0.46-0.78, P < 0.001).In patients with AF and LA enlargement, CAVI is independently associated with LA reverse remodeling after catheter ablation.

Impact of nutritional status on prognosis in acute myocardial infarction patients undergoing percutaneous coronary intervention.

BACKGROUND: Malnutrition affects the prognosis of cardiovascular disease. Acute myocardial infarction (AMI) has been a major cause of death around the world. Thus, we investigated the impact of malnutrition as defined by Geriatric Nutritional Risk Index (GNRI) on mortality in AMI patients. METHODS: In 268 consecutive AMI patients who underwent percutaneous coronary intervention (PCI), associations between all-cause death and baseline characteristics including malnutrition (GNRI < 92.0) and Global Registry of Acute Coronary Events (GRACE) risk score were assessed. RESULTS: Thirty-three patients died after PCI. Mortality was higher in the 51 malnourished patients than in the 217 non-malnourished patients, both within 1 month after PCI (p < 0.001) and beyond 1 month after PCI (p = 0.017). Multivariate Cox proportional hazards regression modelling using age, left ventricular ejection fraction and GRACE risk score showed malnutrition correlated significantly with all-cause death within 1 month after PCI (hazard ratio [HR] 7.04; 95% confidence interval [CI] 2.30-21.51; p < 0.001) and beyond 1 month after PCI (HR 3.10; 95% CI 1.70-8.96; p = 0.037). There were no significant differences in area under the receiver-operating characteristic (ROC) curve between GRACE risk score and GNRI for predicting all-cause death within 1 month after PCI (0.90 vs. 0.81; p = 0.074) or beyond 1 month after PCI (0.69 vs. 0.71; p = 0.87). Calibration plots comparing actual and predicted mortality confirmed that GNRI (p = 0.006) was more predictive of outcome than GRACE risk score (p = 0.85) beyond 1 month after PCI. Furthermore, comparison of p-value for interaction of malnutrition and GRACE risk score for all-cause death within 1 month after PCI, beyond 1 month after PCI, and the full follow-up period after PCI were p = 0.62, p = 0.64 and p = 0.38, respectively. CONCLUSIONS: GNRI may have a potential for predicting the mortality in AMI patients especially in beyond 1 month after PCI, separate from GRACE risk score. Assessment of nutritional status may help stratify the risk of AMI mortality.

Prognostic impact of malnutrition on cardiovascular events in coronary artery disease patients with myocardial damage.

BACKGROUND: Stable coronary artery disease (CAD) patients with myocardial damage have a poor prognosis compared to those without myocardial damage. Recently, malnutrition has been reported to affect the prognosis of cardiovascular diseases. However, the effects of malnutrition on prognosis of CAD patients with myocardial damage remains uncertain. We investigated the effects of malnutrition on prognosis of CAD patients with myocardial damage who received percutaneous coronary intervention (PCI). METHODS: Subjects comprised 241 stable CAD patients with myocardial damage due to myocardial ischemia or infraction. Patients underwent successful revascularization for the culprit lesion by PCI using second-generation drug-eluting stents and intravascular ultrasound. The geriatric nutritional risk index (GNRI), which is widely used as a simple method for screening nutritional status using body mass index and serum albumin, was used to assess nutritional status. Associations between major cardiovascular and cerebrovascular events (MACCE) and patient characteristics were assessed. RESULTS: Mean GNRI was 100 ± 13, and there were 55 malnourished patients (23%; GNRI < 92) and 186 non-malnourished patients (77%). MACCE occurred within 3 years after PCI in 42 cases (17%), including 34 deaths (14%), and the malnourished group showed a higher rate of MACCE (38%) compared with the non-malnourished group (11%, p < 0.001). Univariate Cox proportional hazards analyses showed that MACCE was associated with age [hazard ratio (HR), 1.04; 95% confidence interval (CI), 1.04-1.07; p = 0.004], prior heart failure (HR 2.35; 95% CI 1.10-5.01; p = 0.027), high-sensitivity C-reactive protein (HR 1.08; 95% CI 1.03-1.11; p < 0.001), hemodialysis (HR 2.63; 95% CI 1.51-4.58; p < 0.001) and malnutrition (HR 3.69; 95% CI 2.11-6.42; p < 0.001). Multivariate Cox proportional hazards analysis revealed hemodialysis (HR 2.17; 95% CI 1.19-3.93; p = 0.011) and malnutrition (HR 2.30; 95% CI 1.13-4.67; p = 0.020) as significantly associated with MACCE. Furthermore, Cox proportional hazards models using malnutrition and hemodialysis revealed that patients with malnutrition and hemodialysis were at greater risk of MACCE after PCI than patients with neither malnutrition nor hemodialysis (HR 6.91; 95% CI 3.29-14.54; p < 0.001). CONCLUSIONS: In CAD patients with myocardial damage, malnutrition (GNRI < 92) represents an independent risk factor for MACCE. Assessment of nutritional status may help stratify the risk of cardiovascular events and encourage improvements in nutritional status.

Current Understanding of the Role of Frailty in Cardiovascular Disease.

The elderly population is increasing because of increasing life expectancy, and the prevalence of frailty increases with age. Frailty commonly coexists with cardiovascular diseases (CVDs), such as coronary artery disease (CAD), heart failure (HF), aortic stenosis (AS), and atrial fibrillation (AF). Frail patients who undergo revascularization for CAD have higher complication rates; those with HF have a high prevalence of poor outcomes, and those with AF are vulnerable to increased stroke incidence. Moreover, frailty and asymptomatic severe AS were independent factors for mortality. The presence of frailty can lead to poor clinical outcomes, and frailty has been identified as a risk factor for mortality. Thus, the identification of frail patients who are at higher risks of disability and adverse clinical outcomes is important. In this review, the relationship between frailty and CVD is appraised and optimal treatments for frail patients are discussed.

Management instructions for elderly patients with hypertension.

Aim: To compare the understanding of hypertension and antihypertensive treatment in Japanese patients (aged <75 years vs. ≥75 years) with blood pressure (BP) targets as per the 2014 Japanese guidelines.Methods: A 10-question survey was administered before and after treatment.Results: Majority of patients aged ≥75 years did not achieve their BP targets (75%); >50% of these patients had little knowledge of hypertension and poor understanding of their physician's explanation of it.Conclusions: Elderly patients with hypertension (aged ≥75 years) require daily BP monitoring and detailed and repeated explanation of hypertension and BP targets.

Both gain and loss of Nampt function promote pressure overload-induced heart failure.

The heart requires high-energy production, but metabolic ability declines in the failing heart. Nicotinamide phosphoribosyl-transferase (Nampt) is a rate-limiting enzyme in the salvage pathway of nicotinamide adenine dinucleotide (NAD) synthesis. NAD is directly involved in various metabolic processes and may indirectly regulate metabolic gene expression through sirtuin 1 (Sirt1), an NAD-dependent protein deacetylase. However, how Nampt regulates cardiac function and metabolism in the failing heart is poorly understood. Here we show that pressure-overload (PO)-induced heart failure is exacerbated in both systemic Nampt heterozygous knockout (Nampt+/-) mice and mice with cardiac-specific Nampt overexpression (Tg-Nampt). The NAD level declined in Nampt+/- mice under PO (wild: 377 pmol/mg tissue; Nampt+/-: 119 pmol/mg tissue; P = 0.028). In cultured cardiomyocytes, Nampt knockdown diminished mitochondrial NAD content and ATP production (relative ATP production: wild: 1; Nampt knockdown: 0.56; P = 0.0068), suggesting that downregulation of Nampt induces mitochondrial dysfunction. On the other hand, the NAD level was increased in Tg-Nampt mice at baseline but not during PO, possibly due to increased consumption of NAD by Sirt1. The expression of Sirt1 was increased in Tg-Nampt mice, in association with reduced overall protein acetylation. PO-induced downregulation of metabolic genes was exacerbated in Tg-Nampt mice. In cultured cardiomyocytes, Nampt and Sirt1 cooperatively suppressed mitochondrial proteins and ATP production, thereby promoting mitochondrial dysfunction. In addition, Nampt overexpression upregulated inflammatory cytokines, including TNF-α and monocyte chemoattractant protein-1. Thus endogenous Nampt maintains cardiac function and metabolism in the failing heart, whereas Nampt overexpression is detrimental during PO, possibly due to excessive activation of Sirt1, suppression of mitochondrial function, and upregulation of proinflammatory mechanisms.NEW & NOTEWORTHY Nicotinamide phosphoribosyl-transferase (Nampt) is a rate-limiting enzyme in the salvage pathway of nicotinamide adenine dinucleotide synthesis. We demonstrate that pressure overload-induced heart failure is exacerbated in both systemic Nampt heterozygous knockout mice and mice with cardiac-specific Nampt overexpression. Both loss- and gain-of-function models exhibited reduced protein acetylation, suppression of metabolic genes, and mitochondrial energetic dysfunction. Thus endogenous Nampt maintains cardiac function and metabolism in the failing heart, but cardiac-specific Nampt overexpression is detrimental rather than therapeutic.

Aging and Autophagy in the Heart.

The aging population is increasing in developed countries. Because the incidence of cardiac disease increases dramatically with age, it is important to understand the molecular mechanisms through which the heart becomes either more or less susceptible to stress. Cardiac aging is characterized by the presence of hypertrophy, fibrosis, and accumulation of misfolded proteins and dysfunctional mitochondria. Macroautophagy (hereafter referred to as autophagy) is a lysosome-dependent bulk degradation mechanism that is essential for intracellular protein and organelle quality control. Autophagy and autophagic flux are generally decreased in aging hearts, and murine autophagy loss-of-function models develop exacerbated cardiac dysfunction that is accompanied by the accumulation of misfolded proteins and dysfunctional organelles. On the contrary, stimulation of autophagy generally improves cardiac function in mouse models of protein aggregation by removing accumulated misfolded proteins, dysfunctional mitochondria, and damaged DNA, thereby improving the overall cellular environment and alleviating aging-associated pathology in the heart. Increasing lines of evidence suggest that autophagy is required for many mechanisms that mediate lifespan extension, such as caloric restriction, in various organisms. These results raise the exciting possibility that autophagy may play an important role in combating the adverse effects of aging in the heart. In this review, we discuss the role of autophagy in the heart during aging, how autophagy alleviates age-dependent changes in the heart, and how the level of autophagy in the aging heart can be restored.

Questionnaire Survey From the Viewpoint of Concordance in Patient and Physician Satisfaction Concerning Hypertensive Treatment in Elderly Patients　- Patients Voice Study.

BACKGROUND: Patient-physician concordance is an important concern in the treatment of elderly patients with hypertension (HT). Treatment that considers concordance is necessary for mutual understanding and therapeutic satisfaction between patients and physicians. However, there have been no studies addressing concordance that objectively analyzed both patient and physician satisfaction before and after treatment.Methods and Results:An exploratory open-label, multicenter, intervention study was conducted. Patients with HT undergoing treatment with angiotensin-receptor blocker (ARB) or a calcium-channel blocker (CCB) monotherapy were enrolled. Medication was switched to an ARB/CCB combination tablet and taken for 12 weeks. Physicians and patients participated in satisfaction surveys concerning treatment. Discrepancies in satisfaction levels between patients and physicians were found at baseline for the following survey items: treatment, involvement in treatment, understanding of HT, reliance, medication, and blood pressure. After treatment, the satisfaction levels of both patients and physicians increased; discrepancies in satisfaction between the groups also improved. CONCLUSIONS: The rates of satisfaction were relatively higher for patients compared with physicians at baseline. After HT treatment addressing concordance, both patient and physician satisfaction rates and the gap in satisfaction rates between patients and physicians improved. This indicates that addressing concordance has clinical significance in the treatment of elderly HT patients. (UMIN000017270).

Drp1-Dependent Mitochondrial Autophagy Plays a Protective Role Against Pressure Overload-Induced Mitochondrial Dysfunction and Heart Failure.

BACKGROUND: Mitochondrial autophagy is an important mediator of mitochondrial quality control in cardiomyocytes. The occurrence of mitochondrial autophagy and its significance during cardiac hypertrophy are not well understood. METHODS AND RESULTS: Mice were subjected to transverse aortic constriction (TAC) and observed at multiple time points up to 30 days. Cardiac hypertrophy developed after 5 days, the ejection fraction was reduced after 14 days, and heart failure was observed 30 days after TAC. General autophagy was upregulated between 1 and 12 hours after TAC but was downregulated below physiological levels 5 days after TAC. Mitochondrial autophagy, evaluated by electron microscopy, mitochondrial content, and Keima with mitochondrial localization signal, was transiently activated at ≈3 to 7 days post-TAC, coinciding with mitochondrial translocation of Drp1. However, it was downregulated thereafter, followed by mitochondrial dysfunction. Haploinsufficiency of Drp1 abolished mitochondrial autophagy and exacerbated the development of both mitochondrial dysfunction and heart failure after TAC. Injection of Tat-Beclin 1, a potent inducer of autophagy, but not control peptide, on day 7 after TAC, partially rescued mitochondrial autophagy and attenuated mitochondrial dysfunction and heart failure induced by overload. Haploinsufficiency of either drp1 or beclin 1 prevented the rescue by Tat-Beclin 1, suggesting that its effect is mediated in part through autophagy, including mitochondrial autophagy. CONCLUSIONS: Mitochondrial autophagy is transiently activated and then downregulated in the mouse heart in response to pressure overload. Downregulation of mitochondrial autophagy plays an important role in mediating the development of mitochondrial dysfunction and heart failure, whereas restoration of mitochondrial autophagy attenuates dysfunction in the heart during pressure overload.

Endogenous Drp1 mediates mitochondrial autophagy and protects the heart against energy stress.

RATIONALE: Both fusion and fission contribute to mitochondrial quality control. How unopposed fusion affects survival of cardiomyocytes and left ventricular function in the heart is poorly understood. OBJECTIVE: We investigated the role of dynamin-related protein 1 (Drp1), a GTPase that mediates mitochondrial fission, in mediating mitochondrial autophagy, ventricular function, and stress resistance in the heart. METHODS AND RESULTS: Drp1 downregulation induced mitochondrial elongation, accumulation of damaged mitochondria, and increased apoptosis in cardiomyocytes at baseline. Drp1 downregulation also suppressed autophagosome formation and autophagic flux at baseline and in response to glucose deprivation in cardiomyocytes. The lack of lysosomal translocation of mitochondrially targeted Keima indicates that Drp1 downregulation suppressed mitochondrial autophagy. Mitochondrial elongation and accumulation of damaged mitochondria were also observed in tamoxifen-inducible cardiac-specific Drp1 knockout mice. After Drp1 downregulation, cardiac-specific Drp1 knockout mice developed left ventricular dysfunction, preceded by mitochondrial dysfunction, and died within 13 weeks. Autophagic flux is significantly suppressed in cardiac-specific Drp1 knockout mice. Although left ventricular function in cardiac-specific Drp1 heterozygous knockout mice was normal at 12 weeks of age, left ventricular function decreased more severely after 48 hours of fasting, and the infarct size/area at risk after ischemia/reperfusion was significantly greater in cardiac-specific Drp1 heterozygous knockout than in control mice. CONCLUSIONS: Disruption of Drp1 induces mitochondrial elongation, inhibits mitochondrial autophagy, and causes mitochondrial dysfunction, thereby promoting cardiac dysfunction and increased susceptibility to ischemia/reperfusion.

The Impact of Autophagy on Cardiovascular Senescence and Diseases.

The risk of cardiovascular disease increases with age, causing chronic disability, morbidity, and mortality in the elderly. Cardiovascular aging and disease are characterized by heart failure, cardiac ischemia-reperfusion injury, cardiomyopathy, hypertension, arterial stiffness, and atherosclerosis. As a cell ages, damaged organelles and abnormal proteins accumulate. A system for removing these cytoplasmic substrates is essential for maintaining homeostasis. Autophagy assists tissue homeostasis by forming a pathway by which these substances are degraded. Growing evidence suggests that autophagy plays a role in age-related and disease states of the cardiovascular system, and it may even be effective in preventing or treating cardiovascular disease. On the other hand, overexpression of autophagy in the heart and arteries can produce detrimental effects. We summarize the current understanding of the close relationship between autophagy and cardiovascular senescence.

Molecular mechanisms mediating mitochondrial dynamics and mitophagy and their functional roles in the cardiovascular system.

Mitochondria are essential organelles that produce the cellular energy source, ATP. Dysfunctional mitochondria are involved in the pathophysiology of heart disease, which is associated with reduced levels of ATP and excessive production of reactive oxygen species. Mitochondria are dynamic organelles that change their morphology through fission and fusion in order to maintain their function. Fusion connects neighboring depolarized mitochondria and mixes their contents to maintain membrane potential. In contrast, fission segregates damaged mitochondria from intact ones, where the damaged part of mitochondria is subjected to mitophagy whereas the intact part to fusion. It is generally believed that mitochondrial fusion is beneficial for the heart, especially under stress conditions, because it consolidates the mitochondria's ability to supply energy. However, both excessive fusion and insufficient fission disrupt the mitochondrial quality control mechanism and potentiate cell death. In this review, we discuss the role of mitochondrial dynamics and mitophagy in the heart and the cardiomyocytes therein, with a focus on their roles in cardiovascular disease. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease".

Broad suppression of NADPH oxidase activity exacerbates ischemia/reperfusion injury through inadvertent downregulation of hypoxia-inducible factor-1α and upregulation of peroxisome proliferator-activated receptor-α.

RATIONALE: NADPH oxidase (Nox) 2 and Nox4 are major components of the Nox family which purposefully produce reactive oxidative species, namely O2(-) and H2O2, in the heart. The isoform-specific contribution of Nox2 and Nox4 to ischemia/reperfusion (I/R) injury is poorly understood. OBJECTIVE: We investigated the role of Nox2 and Nox4 in mediating oxidative stress and myocardial injury during I/R using loss-of-function mouse models. METHODS AND RESULTS: Systemic (s) Nox2 knockout (KO), sNox4 KO, and cardiac-specific (c) Nox4 KO mice were subjected to I/R (30 minutes/24 hours, respectively). Both myocardial infarct size/area at risk and O2(-) production were lower in sNox2 KO, sNox4 KO, and cNox4 KO than in wild-type mice. Unexpectedly, however, the myocardial infarct size/area at risk was greater, despite less O2(-) production, in sNox2 KO+cNox4 KO (double-KO) mice and transgenic mice (Tg) with cardiac-specific expression of dominant-negative Nox, which suppresses both Nox2 and Nox4, than in wild-type or single KO mice. Hypoxia-inducible factor-1α was downregulated whereas peroxisome proliferator-activated receptor-α was upregulated in Tg-dominant-negative Nox mice. A cross with mice deficient in prolyl hydroxylase 2, which hydroxylates hypoxia-inducible factor-1α, rescued the I/R injury and prevented upregulation of peroxisome proliferator-activated receptor-α in Tg-dominant-negative Nox mice. A cross with peroxisome proliferator-activated receptor-α KO mice also attenuated the injury in Tg- dominant-negative Nox mice. CONCLUSIONS: Both Nox2 and Nox4 contribute to the increase in reactive oxidative species and injury by I/R. However, low levels of reactive oxidative species produced by either Nox2 or Nox4 regulate hypoxia-inducible factor-1α and peroxisome proliferator-activated receptor-α, thereby protecting the heart against I/R, suggesting that Noxs also act as a physiological sensor for myocardial adaptation.

Relationship between defecation status and blood pressure level or blood pressure variability.

Blood pressure variability is an independent predictor of cardiovascular disease. Defecation status has also been associated with the risk of developing cardiovascular disease. This study aimed to investigate the association between blood pressure variability and defecation status. A total of 184 participants who could measure their home blood pressure for at least 8 days monthly, both at baseline and 1 year later, were included in this study. All participants had their home blood pressure measured using HEM-9700T (OMRON Healthcare). Day-to-day variability of systolic blood pressure was assessed using the coefficient of variation of home systolic blood pressure during 1 month. Data on defecation status was obtained using a questionnaire survey. Eighty-nine patients had an elevated coefficient of variation at 1 year. The proportion of participants with elevated coefficient of variation at 1 year was significantly higher in the no daily bowel movement group than in the daily bowel movement group (72% vs. 42%, P = 0.001). In multivariable logistic regression analysis with the elevated coefficient of variation at 1 year as the objective variable and age, sex, no daily bowel movement, taking medications, including antihypertensive drugs, laxatives, and intestinal preparations, and coefficient of variation at baseline as independent variables, no daily bowel movement was independently associated with the elevated coefficient of variation at 1 year (odds ratio: 3.81, 95% confidence interval: 1.64-8.87, P = 0.0019). In conclusion, no daily bowel movement was independently associated with elevated day-to-day blood pressure variability at 1 year. Relationship between defecation status and blood pressure level or blood pressure variability.